Chronic diseases of the brain such as Alzheimer's disease (AD) impact an estimated 5 million individuals in the US. While progress has been made in identifying specific mutated genes that initiate a neurodegenerative disease process, we have limited information on etiology of many neurodegenerative diseases when a specific gene or agent cannot be identified. Importantly, most mouse models on neurodegenerative diseases use mutated genes, despite the fact that human mutations account for a very low percentage of affected individuals. Chronic diseases of the brain feature an innate immune response that contributes to the disease process. Since essential differences exist between innate immune function in mice and in humans, we have generated a novel "humanized" mouse model that expresses the human NOS2 gene in place of the mouse NOS2 gene (HuNOS2/mNOS2-/-). We have also crossed this mouse to an APP transgenic mouse that expresses mutated human amyloid precursor protein (APPSwDI/huNOS2/mNOS2-/-). We show that by reducing NO levels in mice to levels more typical of people, we now observe features of AD-like disease progression that are not found in other mouse models of AD. Murine and human conditions also differ by the presence of environmental factors such as stress and over- nutrition that initiate/accelerate chronic diseases including metabolic syndrome (MS). We hypothesize that metabolic syndrome will similarly accelerate the development of neurodegeneration. Using our novel "humanized" mice, we propose to expose mice to an environmental stressor that is known to lead to metabolic syndrome in mice. This "humanized" environment incorporates high fat/high sugar diet with cold-water stress. Use of the HuNOS2/mNOS2-/- mouse will allow us to potentially demonstrate for the first time in a mouse model that full AD-like pathology can be induced by environmental stress in the absence of mutated human genes known to produce AD in humans. Use of the APPSwDI /huNOS2/ mNOS2-/- will allow us to determine if onset and/or disease progression are altered in mice that express human disease genes. PUBLIC HEALTH RELEVANCE: The proposed research will study the action of environmental factors on the onset and progress of chronic neurodegenerative disease in a novel "humanized" mouse model.